Method of treating or preventing coccidiosis

ABSTRACT

A method of treating or preventing coccidiosis in poultry which comprises orally administering to poultry an effective coccidiosis treatment or preventing amount of a compound of the Formula (I) or a pharmacologically acceptable acid addition salt thereof WHEREIN R and R&#39;&#39; are the same or different and each is a hydrogen atom, loweralkyl, cyclohexyl, benzyl, phenyl, halogen substituted phenyl, or loweralkoxyloweralkyl, R2 is lower alkyl and n has an integral value from 1 to 8. A composition comprising the compound of formula I and a pharmacologically acceptable carrier.

O United States Patent [151 3,674,873

Barrett 1 July 4, 1972 [54] METHOD OF TREATING 0R PrimaryExaminer-Albert T. Meyers PREVENTING COCCIDIOSIS AssistantExaminerVincent D. Turner Attorney-Dike, Roberts & Cushman [72]Inventor: Paul Anthony Barrett, London, England [73] Assignee: BurroughsWellcome Co. [57] ABSTRACT 22 Filed; 7 1970 A method of treating orpreventing coccidiosis in poultry which comprises orally administeringto poultry an effective [21] PP 53,040 coccidiosis treatment orpreventing amount of a compound of the Formula (I) or apharmacologically acceptable acid addi- Related US. Application Datation salt thereof [62] Division of Ser. No. 550,934, May 18, 1966, Pat.No.

RC=N-NH-CS-NH-[CH2]nN NR2 [30] Foreign Application Priority Data May 25,1965 Great Britain ..22,006/65 R C=N NH-CS-NH-[CH2].,N N-R [52] U.S.CI..424/250 wherein R and R are the same or different and each is ahydrogen atom, loweralkyl cyclohexyl benzyl, phenyl, halogen substitutedphenyl, or Ioweralkoxyloweralkyl, R is Rem-wees Cited lower alkyl and nhas an integral value from 1 to 8. A composi- UNITED STATES PATENTS tioncomprising the compound of formula 1 and a charmacologically acceptablecarrier. 3,577,421 5/1971 Barrett ..260/268 R 18 Claims, No DrawingsMETHOD OF TREATING R PREVENTING COCCIDIOSIS This application is adivision of U.S. Pat. application Ser. No. 550,934, filed May 18, 1966,now U.S. Pat. No. 3,577,421.

This invention relates to a-dithiosemicarbazones which have activityagainst coccidiosis.

The compounds are of Formula (I) below:

wherein R and R are the same or different and each is a hydrogen atom oran alkyl, cyclohexyl, benzyl, phenyl, halogen substituted phenyl, oralkyloxyalkyl group, R is an alkyl group, and n has an integral valuefrom 1 to 8, preferably 2 to 5.

In the above definition, alkyl means a straight or branched chain alkylgroup ofone to six carbon atoms.

The compounds are basic and may be presented as acid addition salts: theacid moiety should be chosen so that the acid addition salt is stillpharmacologically acceptable to animals, but otherwise the acid used isof no consequence; for example hydrochloric acid, oxalic acid, orsulphuric acid may be used in the ratio of one to four equivalents ofacid to one equivalent of a compound of Formula (I). However, there isno apparent advantage in using acid addition salts and the basiccompounds of Formula (I) are preferred.

Those compounds wherein both R and R are hydrogen atoms are less activethan the other compounds of Formula (I). The preferred compounds arethose wherein R and R are the same or different and each is a methyl orphenyl group. The particularly preferred compounds are acetylbenzoyldi-4- B-(4-methylpiperazinyl-l )ethylthiosemicarbazone (668C64),acetylbenzoyl di-4-,B-(4-ethylpiperazinyl-l )ethylthiosemicarbazone(560C65), biacetyl di-4-,B-(4-ethylpiperazinyll)ethylthiosemicarbazone(559C65) and acetylbenzoyl di-4- B-( 4-n-propylpiperazinyl-1)ethylthiosemicarbazone l50C66): an especially preferred compound isacetylbenzoyl di-4-B-( 4-methylpiperazinyl-I )ethylthiosemicarbazone,hereinafter referred to as 668C6 1.

Thus in one aspect this invention provides the compounds of Formula (I)and in particular those stated above to be preferred.

Coccidiosis is a disease of considerable economic importance in domesticanimals throughout the world, particularly in all forms of poultry, andis caused by members of the genera Eimeria and Isospora of the taxonomicgroup Coccidia.

The activity of the compounds was first detected by administering thebasic compounds in the diet to chicks infected with Eimeria Ienella; thecompounds were effective in halting the development of the disease. Thebasic compounds were then administered at concentrations between 0.003and 0.05 percent w/w of the food to birds artificially infected withEimeria spp. As an illustration of the degree of activity, 668C154 wasprophylactically active at 0.003 to 0.007 percent against E. tenella andE. maxima and at 0.005 to 0.015 percent against E. acervalina and E.necatrix. This compound and other compounds of Formula (I) were alsoactive against other forms of coccidia and in other animals thanpoultry. Higher doses were needed when using some of the less preferredcompounds of Formula (I), and when acid addition salts were used thedoses had to be correspondingly increased to allow for the inactive acidpart of the molecule.

If only E. tenella and E. maxima are to be controlled doses of 0.005percent w/w of 668C64 in the food or approximately 50 gm. of drug perton of food can be successfully used under controlled conditions, butunder field conditions doses up to 100 gm are preferred. If otherspecies are to be controlled higher doses are needed such as to 200 gmof drug per ton of food.

However the compounds of Fonnula (I) may be added to other coccidiostatsto obtain a broad spectrum coccidiostat. Thus for example the compoundsmay be mixed with sulphaquinoxaline or with a synergistic combination ofsulphaquinoxaline and diaveridine or with other known coccidiostats. Thedoses needed will then vary according to the quantity of the othercoccidiostatic agent present and its degree of activity. The effects ofthe compounds of Formula (I) with other coccidiostats seem to indicatethat the activities are purely additive.

The compounds of Formula (I) are administered orally and can bepresented alone, in a pharmaceutical formulation, as additive to theanimals food or drink or as a final food or drink containing thecompound.

The dose of compound required is such that it is not normally convenientto administer the compound alone except under laboratory conditions.Examples of pharmaceutical formulations containing a compound of Formula(I) are tablets, capsules, granules, powders, suspensions, solutions andemulsions which may contain diluents, binding agents, dispersing agents,surface active agents, lubricating agents, coating materials, flavoringagents, coloring agents, solvents, thickening agents, suspending agentsor other pharmaceutically acceptable additives and these formulationsmay be presented in unit dose form or multi-dose form. The formulationsmay also contain other coccidiostats or other active additives such asantibiotics, vitamins, minerals or other therapeutic agents, thoughspecial care must be taken to ensure that the ingredients arecompatible.

However, the compounds are preferably presented as an additive to bemixed with the animals food or drink. This additive may itself be apharmaceutical formulation as described above or it may be aconcentrated food pre-mix or drink additive which contains the compoundof Formula (I) in a diluted form compared with the compound alone but ina more concentrated form than will be finally administered to theanimal. This method of presentation is particularly suitable for usewith poultry. As a food pre-mix, the compound together with any othercompatible active agents such as other coccidiostats, antibiotics,vitamins or minerals which are required, are mixed with carriers ordiluents such as bran, ground maize, barley or other corn, wheat shorts,husks, edible vegetable substances, flour, soya bean flour, crumbs andsimilar food stuffs and possibly other diluents such as crushedlimestone and grits, and the components are thoroughly mixed byconventional techniques such as grinding, stirring, milling or tumbling.The mixture is then presented as a powder or other small particulatecomposition or it may be further processed into pellets or similar foodadditives. This food premix is then added to other foods at theconcentration of say 1 lb. of pre-mix per cwt. of food depending on theconcentration of the active components in the pre-mix. It will beappreciated that pre-mixes can be prepared at all concentrations betweenthe compound of Formula (I) with traces of diluents up to foodspractically in their final form. Alternatively, of course, ready mixedfoods containing the compound of Formula (I) in a form suitable fordirect administration to the birds may be produced. If the compounds ofFormula (I) are presented as drink additives they are normally in theform of their acid addition salts. The substance may be presented in afinely divided solid form, optionally together with other solubleadditives, or it may be presented as a concentrate containing thecompound in solution in suitable solvents. This powder or concentrate isthen added to the water. This method of presentation in the form of adrink additive is not as suitable as a food additive because the uptakeof drink by poultry is more variable than food intake, and henceprophylactic dosing is not as accurate.

Thus in another aspect this invention provides a method for theprevention of coccidiosis in domestic animals, particularly in poultry,which comprises orally administering a compound of Formula (I) to theanimal or bird at risk.

In another aspect the invention provides formulations for oraladministration to animals which contain a compound of Formula (I).

In yet another aspect the invention provides a method of making suchformulations which comprises incorporating the compound into theformulation by known pharmaceutical or food preparation techniques.

Particularly the invention provides the above embodiments wherein thecompound of Formula (I) is one of the preferred compounds.

The compounds of Formula (I) are prepared by reacting in acid solution aglyoxal of Formula (II) with two molecular proportions of a4-substituted thiosemicarbazide of Formula (III).

wherein R, R, R and n have the above defined meanings. The proportionsof the Compounds (II) and (III) should preferably be calculated to be inthe correct ratio of 1 equivalent of (II) to 2 equivalents of(IIl). Ifexcess of (II) is present some monothiosemicarbazone may be produced andifan excess of(IIl) is present this acts as a contaminant in thepurification of the product of formula (I); otherwise the proportionsare not critical. The choice of solvent is not critical and any suitablesolvent which doesn't enter into the reaction may be used, thoughethanol is convenient and is preferred. The thiosemicarbazides ofFormula (III) are basic substances and the pH of the mixture ofreactants and solvents should be on the acid side; very strong acidsmight give rise to side reactions and so weakly acid solutions arepreferred, with hydrochloric acid as a convenient acid to use, thoughthis is not critical. Many of the diketones of Formula (II) are oilswhich do not necessarily go into solution before the reaction, andreferences to suitable solvents should be construed in the context ofthe compounds of Formula (Ill) and the products of Formula (I). Thereaction is effected by heating the reactants together in the presenceof the acidified solvent. With some glyoxals of Formula (II) thereaction is complete in a few minutes but with less soluble glyoxals itcan take longer: in practice heating for one-half hour ensures that thereaction is complete. The products of Formula (I) are usually soluble inthe form of their acid addition salts in the hot acidic solvent medium.Thus the mixture may need to be cooled and made basic to separate theproduct. A less satisfactory method is to evaporate off the solventleaving the acid addition salt of the compound of Formula (I). Thecompounds of Formula (I) may be purified by recrystallization from asuitable solvent such as ethyl acetate or by other conventionaltechniques.

Thus in another aspect this invention provides a method of preparing acompound of Formula (I) substantially as described above.

Alternatively the compounds of Formula (I) may be synthesized byreacting one molecule of the appropriate glyoxalbis(methylcarbodithioylhydrazone) of Formula (IV) with two molecules ofthe appropriate w-4'-alkylpiperazin-l ylalkylamine of Formula (V),thereby eliminating methylmercaptan to produce the dithiosemicarbazoneof Formula (I).

The reaction may be effected by heating the reactants together,preferably in a suitable solvent. Most of the compounds of Formula (IV)are solids and most of the amines of Formula (V) are liquids. If asolvent is used it should be chosen as one which can not enter into thereaction and which has a boiling point below that of the amine ofFormula (V), but preferably high enough to allow a suitable reactiontemperature to be used, as the reaction is not always a fast one:ethanol is such a suitable solvent but one should avoid ketones andaldehydes. It is necessary to heat the reactants together for periodsbetween one-half hour and 8 hours to get good yields. The solid productof Formula (I) separates from the solution and after cooling this can befiltered off. The compounds of Formula (IV) which are also solids arenot soluble in hydrochloric acid and any unchanged starting material ofFormula (IV) can be removed from the compounds of Formula (I) bydissolving the product in hydrochloric acid and filtering off thestarting material. The basic compound of Formula (I) can be precipitatedagain by making the solution basic: it can then be purified byconventional techniques. Alternatively the compound of Formula (I) maybe extracted from the initial reaction mixture by distilling off excesssolvent, solvent extracting the product of Formula (I) with a selectivesolvent such as chloroform and recovering and purifying the compound ofFormula (I) by conventional techniques. The former method of working upthe product is preferred.

Thus in yet another aspect this invention provides the above describedalternative synthesis of the compounds of Formula The second synthesisis not as convenient as the first described method.

Having now described the invention, the following examples illustrate inmore detail the preparation of the compounds of Formula (I).

EXAMPLE I la. Preparation of 4-fi-(4-methylpiperazinyll)ethylthiosemicarbazide Acetophenone methylcarbodithioylhydrazone (l 16g.) (prepared by the method of Kazakov and Postovskii, Doklady Akad.Nauk S.S.S.R., 1960, Vol. 134, 824 abstracted in C.A., 1961, 55, 6483")and l-methyl-4-Baminoethylpiperazine (73 g.) in methanol (600 ml.) wereboiled under reflux for 7 hours. The methanol was removed bydistillation in vacuo. The residual solid was sucked free of a littleoily impurity, washed with ml. of ether, and recrystallized from amixture of equal parts of benzene and light petroleum (b.p. 80-l00 C) togive ucetophenone 4-B(4-methylpiperazinyll )ethylthiosemicarbazone ascolorless crystals, m.p. l67-168 C.

Acetophenone 4-fl-(4-methylpiperazinyll)ethylthiosemicarbazone (31.9 g.)was dissolved in water ml.) and concentrated hydrochloric acid (20 ml.)and submitted to steam distillation till no more acetophenone waspresent in the distillate. The pH of the solution before steamdistillation is begun should be about 1-2, and after completion of thedistillation about 2-3. The product in solution is 4-B-(4-methylpiperazinyl- 1 )ethylthiosemicarbazide as its dihydrochloride,acid addition salt.

As an optional step, the solution of 4-B-(4-methylpiperazinyl-l )-ethylthiosemicarbazide dihydrochloride resulting from the steam distillationwas evaporated to dryness in vacuo, the oily residue dried by thedistillation from it of several portions of methanol, and finallyobtained in crystalline form by prolonged boiling with dry methanol. Thecolorless solid was filtered, washed and dried to give4-B-(4-methylpiperazinyll )ethyl thiosemicarbazide dihydrochloride, m.p.180-18l C.

lb. Reaction of acetylbenzoyl with thiosemicarbazide from la) to giveacetylbenzoyl di-4-B-(4-methylpiperazinyll )ethyl-thiosemicarbazoneAcetyl benzoyl (7.4 g.), dissolved in a few ml. of ethanol, was added tothe solution of 4-B-(4-methylpiperazinyl-l )ethyl thiosemicarbazidedihydrochloride resulting from the steam distillation above and themixture was boiled under reflux for one-half hour with vigorousstirring. The solution was cooled and basified strongly by addition of alarge excess of saturated sodium carbonate solution. Thedithiosemicarbazone which separated in gelatinous form, slow to filter,was extracted with chloroform, the chloroform solution dried and thesolvent removed by distillation to give an oil which rapidly solidifiedand was recrystallized (preferably after grinding and washing with alittle ether) from ethyl acetate to give acetylbenzoyl di-4-B-(4-methylpiperazinyl-l )ethylthiosemicarbazone (B.W. ref. no.668C6 1) as almost colorless needles, mp. l8ll82 C.

Alternatively, the required dithiosemicarbazone was separated from somemonothiosemicarbazone, which invariably contaminates it, by solution inthe theoretical amount of ZN-hydrochloric acid necessary to convert toits 10 dihydrochloride, evaporation to dryness, and recrystallizationfrom ethanol containing a little water, to give acetylbenzoyl di-4-B-(4-methylpiperazinyl-l )ethylthiosemicarbazone dihydrochloride as paleyellow plates, mp. l-202 C.

If the optional step of separating the thiosemicarbazide intermediate ofpart la) was carried out, this was then reacted with the theoreticalamount of acetylbenzoyl as described above, to give the requireddithiosemicarbazone (668C64).

EXAMPLES 2-l 3 By the method described in the first paragraph of Examplela) the following novel intermediates of the general formula ether(b.p.60-80C) They were then converted to the appropriatethiosemicarbazide salt as described in the second paragraph of( la).Using one of these intermediates and the appropriately substitutedglyoxal of the formula R'.CO.CO.R the following dithiosemicarbazones ofthe general formula lc"'(:ZNNII(JS'NII[CIIQ]I1N NR2 were prepared by themethods of Example lb).

In most cases it was not necessary to chloroform extract theprecipitated dithiosemicarbazone after basification on the initialreaction solution; the product was simply filtered off and purified byrecrystallization.

EXAMPLE l 7 A hot solution of methyl dithiocarbazinate (42 g.) inethanol ml.) containing 5 drops of concentrated hydrochloric acid wasprepared and to this a solution of diacetyl (14.8 g.) in ethanol (400ml.) was added dropwise with stirring over a period of 15 minutes.Butane 2,3-dione bis-(methylcarbodithioyl hydrazone) began to separateduring the addition. The mixture was heated under reflux for a further 1hour and then the hydrazone was filtered off and washed with hotethanol. It had a melting point of 220 C with decomposition.

A mixture of this butane-2,3-dione bis-(methylcarbodithioyl hydrazone)(4 g.) with l-B-aminoethyl-4-methylpiperazine (5.9 g.) in ethanol (20ml.) was boiled under reflux for 8 hours. During this period the productseparated from solution. After cooling, the mixture was filtered. Thesolid was dissolved in 0.5N-hydr0chloric acid (50 ml.), some insolublematerial was filtered off and discarded, the solution was made basic byaddition of sodium carbonate solution, and the precipitated base wasfiltered off, dried, and recrystallized from cellosolve (see above2-ethoxyethanol) to give butane-2,3-dione di-(4-[3-4'-methyl-lpiperazinoethylthiosemicarbazone) (B.W. ref. no. 667C64) which had amelting point of 259 C with decomposition.

EXAMPLE l8 Benzil bis-( methylcarbodithioyl hydrazone), m.p. 180-l 81 C(decomp.) was prepared by a similar method to that described in thefirst part of Example 17. 12 g. of this were suspended in a mixture of4-methyl-l-B-aminoethylpiperazine (45 g.) and ethanol (45 ml.) and themixture was boiled under reflux for 1 hour. The ethanol was removed bydistillation under a water pump vacuum. The residue was diluted withwater, the oil extracted with chloroform, and the chloroform solutionwashed with water, dried and evaporated, to give a viscous residue. Thelatter was dissolved in a little ethanol. Addition of light petroleum(b.p. 4060 C) precipitated crystalline material which was recrystallizedfrom a mixture of benzene and light petroleum (b.p. 4060 C) to givebenzil di- 4-fl-(4-methylpiperazinyl-l )ethyl-thiosemicarbazone (B.W.ref. no. 176C66) as yellow prisms, m.p. 207-208 C (decomp.)

lclaim:

l. A method of treating coccidiosis in poultry suffering fromcoccidiosis which comprises orally administering to the poultry aneffective coccidiosis treating amount of a compound of the formula,

Example ref. no. R R n R Solvent for crystallisation M.p., 0.

118066 11 II 2 Me Ethanol 228-229 (decomp.) 119C66 11 Me 2 Me Aq.ethanol 234-235 (decomp.)

176C613 ]l ([1113 2 -165 (decomp.)

EtOCH 152C6G II Cyclohexyl 2 Ethyl acetate 189490 (decomp.) 667064 Me Me2 269 (decomp.) 559C Me Me 2 253 (decomp.) 149C66 Me Me 2 240 (decomp.)560C635 Me Ph 2 150-151 (decomp.) 150666 Me Ph 2 166-166 (decomp.)169066 Me p-ClPh 2 207-208 (decomp.) 153C66 Me hCH 2 193-195 (decomp.)179066 Ph 0 ii! PhCH-v 2 219 (decomp.) 236C66 Me Me 2 232 (decomp.)38065 Me Me 3 205 (decomp.) 118065 Me Ph 3 140 (decomp.)

1 Diacid oralate. 13.10., (SO-80 C.

*Cellosolve' is the United States registered trademark of Union CarbideLtd. for 2-ethoxyethanol.

wherein R and R are the same or different and each is a hydrogen atom,lower alkyl, cyclohexyl, benzyl, phenyl, halogen substituted phenyl, orlower alkoxy lower alkyl, R is lower alkyl and n has an integral valuefrom 1 to 8 or a pharmacologically acceptable acid addition saltthereof.

2. A method according to claim 1 where R and R are the same or differentand each is a methyl or phenyl group.

7 3. A method according to claim 1, in which the compound isacetylbenzoyl di-4-B-(4-methylpiperazinyl-l ethylthiosemicarbazone.

4. A method according to claim 1, in which the compound is acetylbenzoyldi-4-B-(4-ethylpiperazinyl-l) ethylthiosemicarbazone.

5. A method according to claim 1, in which the compound is biacetyldi-4-B-(4-ethylpiperazinyl-l) ethylthiosemicarbazone.

6. A method according to claim 1, in which the compound is acetylbenzoyldi-4-B-(4-n-propylpiperazinyl-l) ethylthiosemicarbazone.

7. A method of preventing coccidiosis in poultry which comprises orallyadministering to the poultry an effective coccidiosis preventing amountof a compound of the formula 10. A method according to claim 7, in whichthe'compound is acetylbenzoyl di-4-B-(4-ethylpiperazinyllethylthiosemicarbazone.

1 1. A method according to claim 7, in which the compound is biacetyldi-4-B-(4-ethylpiperazinyl-l) ethylthiosemicarbazone.

12. A method according to claim 7, in which the compound isacetylbenzoyl di-4-B-(4-n-propylpiperazinyl-l ethylthiosemicarbazone.

13. A coccidiostat composition which comprises a pharmacologicallyacceptable carrier and an effective coccidiostatic amount of a compoundof the formula wherein R and R are the same or different and each is ahydrogen atom, lower alkyl, cyclohexyl, benzoyl, phenyl,

halogen substituted phenyl, or lower alkoxy lower alkyl, R is loweralkyl and n has an integral value from 1 to 8 or a pharmacologicallyacceptable acid addition salt thereof.

14. A composition according to claim 13, where R and R are the same ordifferent and each is a methyl or phenyl group.

15. A composition according to claim 13, in which the compound isacetylbenzoyl di-4-B-(4-methylpiperazinyl-l ethylthiosemicarbazone.

16. A composition according to claim 13, in which the compound isacetylbenzoyl di-4-B-(4-ethylpiperazinyl-l) ethylthiosemicarbazone.

17. A composition according to claim 13, in which the compound isbiacetyl di-4-B-(4-ethylpiperazinyl-l ethylthiosemicarbazone.

18. A composition according to claim 13, in which the compound isacetybenzoyl di-4-B-(4-n-propylpiperazinyl-l ethylthiosemicarbazone.

2. A method according to claim 1 where R and R'' are the same ordifferent and each is a methyl or phenyl group.
 3. A method according toclaim 1, in which the compound is acetylbenzoyldi-4-B-(4-methylpiperazinyl-1) ethylthiosemicarbazone.
 4. A methodaccording to claim 1, in which the compound is acetylbenzoyldi-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone.
 5. A methodaccording to claim 1, in which the compound is biacetyldi-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone.
 6. A methodaccording to claim 1, in which the compound is acetylbenzoyldi-4-B-(4-n-propylpiperazinyl-1) ethylthiosemicarbazone.
 7. A method ofpreventing coccidiosis in poultry which comprises orally administeringto the poultry an effective coccidiosis preventing amount of a compoundof the formula wherein R and R'' are the same or different and each is ahydrogen atom, lower alkyl, cyclohexyl, benzoyl, phenyl, halogensubstituted phenyl, or lower alkoxy lower alkyl, R2 is lower alkyl and nhas an integral value from 1 to 8 or a pharmacologically acceptable acidaddition salt thereof.
 8. A method according to claim 7 where R and R''are the same or different and each is a methyl or phenyl group.
 9. Amethod according to claim 7, in which the compound is acetylbenzoyldi-4-B-(4-methylpiperazinyl-1) ethylthiosemicarbazone.
 10. A methodaccording to claim 7, in which the compound is acetylbenzoyldi-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone.
 11. A methodaccording to claim 7, in which the compound is biacetyldi-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone.
 12. A methodaccording to claim 7, in which the compound is acetylbenzoyldi-4-B-(4-n-propylpiperazinyl-1) ethylthiosemicarbazone.
 13. Acoccidiostat composition which comprises a pharmacologically acceptablecarrier and an effective coccidiostatic amount of a compound of theformula wherein R and R'' are the same or different and each is ahydrogen atom, lower alkyl, cyclohexyl, benzoyl, phenyl, halogensubstituted phenyl, or lower alkoxy lower alkyl, R2 is lower alkyl and nhas an integral value from 1 to 8 or a pharmacologically acceptable acidaddition salt thereof.
 14. A composition according to claim 13, where Rand R'' are the same or different and each is a methyl or phenyl group.15. A composition according to claim 13, in which the compound isacetylbenzoyl di-4-B-(4-methylpiperazinyl-1) ethylthiosemicarbazone. 16.A composition according to claim 13, in which the compound isacetylbenzoyl di-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone. 17.A composition according to claim 13, in which the compound is biacetyldi-4-B-(4-ethylpiperazinyl-1) ethylthiosemicarbazone.
 18. A compositionaccording to claim 13, in which the compound is acetybenzoyldi-4-B-(4-n-propylpiperazinyl-1) ethylthiosemicarbazone.